This invention relates to compounds which are agonists of the progesterone receptor, their preparation and utility.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
Jones, et al, described in U.S. Pat. No.5,688,810 the PR antagonist dihydroquinoline A. 
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). 
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad. Sci., 761, 383, 1995). 
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). 
Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). 
Kuhla, et al, taught the oxindole M as a cardiotonic (WO 86/03749). 
Weber, described the oxindole N for cardiovascular indications (WO 91/06545). 
Fischer, et al, claim a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516). 
R=various
Singh, et al, described the PDE III inhibitor P (J. Med. Chem., 37, 248, 1994). 
Andreani, et al, described the cytotoxic agent Q (Acta. Pharn. Nord., 2, 407, 1990). 
Binder, et al, described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767). 
Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566). 
Bohm, et al, claim the oxindole T as cardiovascular agents (WO 91/06545). 
Bohm, et al, include the generic structure U (WO 91/04974). 
JP 63112584 A contains the generic structure V: 
Boar, et al, described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1). 
Kende, et al, described methodology for preparing 3,3-substituted oxindoles, e.g. X, that was utilized in the present invention (Synth. Commun., 12, 1, 1982). 
This invention provides compounds of the formulae 1 or 2: 
wherein
R1 and R2 are chosen independently from the group of H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl:
or R1 and R2 are joined to form a ring comprising one of the following: xe2x80x94CH2(CH2)nCH2xe2x80x94; xe2x80x94CH2CH2CMe2CH2CH2xe2x80x94; xe2x80x94O(CH2) mCH2xe2x80x94; O(CH2)pOxe2x80x94; xe2x80x94CH2CH2OCH2CH2xe2x80x94; or xe2x80x94CH2CH2N(H or alkyl)CH2CH2xe2x80x94;
m is an integer from 1 to 4;
n is an integer from 1 to 5;
p is an integer from 1 to 4;
or R1 and R2 together comprise a double bond to one of the following: CMe2; C(cycloalkyl), O, C(cyloether).
R3 is selected from H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl or substituted alkynyl, or CORA;
RA is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R4 is selected from H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R5 is selected from the groups a), b) or c):
a) R5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is selected from halogen, OH, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, S(O)alkyl, S(O)2alkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO 2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, CORB, OCORB, NRCCORB;
RB is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
Y and Z are independently selected from H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkyl;
or
b) R5 is a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group of H, halogen, CN, NO2 and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R6is H, or C1 to C3 alkyl; or
c) R5 is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, NO2, lower alkoxy, or CF3;
Q1 is S, NR7, CR8R9;
R7 is selected from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, acyl, substituted acyl, aroyl, substituted aroyl, SO2CF3, OR11 or NR11R12;
R8 and R9 are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, or CO2R10,
R10 is C1 to C3 alkyl; or
CR8R9 comprises a six membered ring as shown by the structure below 
Q2 is selected from the moieties: 
R11, R12 and R13 are independently selected from H. C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl or substituted aroyl or sulfonyl;
or a pharmaceutically acceptable salt thereof.
A preferred list of substituents represented by R11, R12 and R13 in groups of the compounds described herein are H, C1 to C6 alkyl, substituted C1 to C6 alkyl, xe2x80x94C(O)xe2x80x94(C1 to C6 alkyl), xe2x80x94S(O)2xe2x80x94(C1 to C6 alkyl), phenyl or benzyl.
It will be understood that this invention includes all tautomeric forms of the compounds, chemical formulae and substituents described herein.
Two preferred sets of compounds of this invention is depicted by structures 2 and 3, respectively: 
each wherein R5 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, C1 to C3 alkoxy, C1 to C3 alkyl, N02, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl; or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 2 are those wherein R5 is a five membered ring with the structure shown below 
wherein:
U is O, S, or NR6;
R6 is H, or C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 C1 to C3 alkyl, or C1 to C3 alkoxy;
Yxe2x80x2 is from the group of H, F or C1 to C4 alkyl; or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which R5 is a thiophene or furan ring substituted by Xxe2x80x2 and Yxe2x80x2, as described above.
A further preferred subgroup group of compounds of formulas 2 and 3 are those wherein R5 is a six membered ring with the structure: 
wherein X1 is N or CX2,
X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 or NO2;
Q1 is S, NR7, CR8R9;
R7 is from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R8 and R9 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN CO2R10,
R10 is C1 to C3 alkyl;
CR8R9 are within a six membered ring as shown by the structure below 
or pharmaceutically acceptable salt thereof
Still another preferred group of these compounds includes those having the general formulae: 
each wherein R5 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl; or a pharmaceutically acceptable salt thereof.
A further preferred subgroup group of compounds of formulae: 
are those wherein R5 is a six membered ring with the structure: 
wherein X1 is N or CX2,
X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 or NO2;
Q2 is as defined above;
R7 is from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R8 and R9 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN CO2R10,
R10 is C1 to C3 alkyl;
CR8R9 are within a six membered ring as shown by the structure below 
or pharmaceutically acceptable salt thereof
A further preferred set of compounds of this invention is depicted by structure 4, 
Wherein R14 is chosen from the group H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, substituted sulfonyl.
Wherein R5 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CON(alkyl)2, CSN(alkyl)2, CNHNHOH, CNH2NOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof
Another preferred group of formula 4 are those wherein R5 is a five membered ring with the structure shown below 
wherein:
U is O, S, or NR6;
R6 is H, or C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, CONH2, CNHNHOH, CNH2NOH, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, C1 to C3 alkyl, or C1 to C3 alkoxy;
Yxe2x80x2 is from the group of H, F or C1 to C4 alkyl; or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which R5 is a thiophene or furan ring substituted by Xxe2x80x2 and Yxe2x80x2, as described above.
A further preferred subgroup group of compounds of formula 4 are those wherein R5 is a six membered ring with the structure: 
wherein X1 is N or CX2,
X is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 or NO2;
R7 is from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R8 and R9 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN CO2R10,
R10 is C1 to C3 alkyl;
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by structure 
Wherein R5 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, CNHNOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl; or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 5 are those wherein R5 is a five membered ring with the structure shown below. 
wherein:
U is O, S, or NR6;
R6 is H, or C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, C1 to C3 alkyl, or C1 to C3 alkoxy;
Yxe2x80x2 is from the group of H, F or C1 to C4 alkyl; or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which R5 is a thiophene or furan ring substituted by Xxe2x80x2 and Yxe2x80x2, as described above.
A further preferred subgroup group of compounds of formula 5 are those wherein R5 is a six membered ring with the structure: 
wherein X1 is N or CX2,
X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 or NO2;
R7 is from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R8 and R9 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN CO2R10,
R10 is C1 to C3 alkyl;
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by structure 
Wherein R15 is selected from the group H, Me, CO2R, acyl, substituted acyl, aroyl, substituted aroyl, alkyl, substituted alkyl, CN.
Wherein R5 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, CNHNOH, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 6 are those wherein R5 is a five membered ring with the structure shown below 
wherein:
U is O, S, or NR6;
R6 is H, or C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, C1 to C3 alkyl, or C1 to C3 alkoxy;
Yxe2x80x2 is from the group of H, F or C1 to C4 alkyl; or a pharmaceutically acceptable salt thereof.
A further preferred subgroup of the compounds above are those in which R5 is a thiophene or furan ring substituted by Xxe2x80x2 and Yxe2x80x2, as described above.
A further preferred subgroup group of compounds of formula 6 are those wherein R5 is a six membered ring with the structure: 
wherein X1 is N or CX2,
X2 is halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 or NO2;
R7 is from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R8 and R9 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN CO2R10,
R10 is C1 to C3 alkyl;
or pharmaceutically acceptable salt thereof.
A further preferred set of compounds of this invention is depicted by structure 
Wherein R5 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is selected from halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 CNHNOH, C1 to C3 alkoxy, C1 to C3 alkyl, N02, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkyl;
or a pharmaceutically acceptable salt thereof.
Another preferred group of formula 7 are those wherein R5 is a five membered ring with the structure shown below 
wherein:
U is O, S, or NR6;
R6 is H, or C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2, C1 to C3 alkyl, or C1 to C3 alkoxy;
Yxe2x80x2 is from the group of H, F or C1 to C4 alkyl;
or a pharmaceutically acceptable salt thereof
A further preferred subgroup of the compounds above are those in which R5 is a thiophene or furan ring substituted by Xxe2x80x2 and Yxe2x80x2, as described above.
A further preferred subgroup group of compounds of formula 7 are those wherein R, is a six membered ring with the structure: 
wherein X1 is N or CX2,
X2 halogen, CN, CONH2, CSNH2, CONHalkyl, CSNHalkyl, CONalkyl2, CSNalkyl2 or NO2;
R7 is from the group including CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R8 and R9 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, hetero cyclic, substituted hetero cyclic, NO2, CN, or CO 2R10,
R10 is C1 to C3 alkyl;
or pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry xe2x80x2 in Formula 1 and 2 the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon triple bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms.
The term xe2x80x9cacylxe2x80x9d refers to a carbonyl substituent, including both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9csubstituted acylxe2x80x9d refers to an acyl group as just described optionally substituted with from 1 to 6 groups chosen from the list halogen, CN, OH, and NO2.
The term xe2x80x9caroylxe2x80x9d also refers to a carbonyl substituent carrying a phenyl group or a heteroaromatic group. The heteroaromatic groups of this include 2-, 3- or 4-pyridinyl, 2- and 3-furanyl, 2- or 3-thiophenyl, or 2- or 4-pyrimidinal. The term xe2x80x9csubstituted aroylxe2x80x9d also refers to an aroyl group as just described optionally substituted with from 1 to 6 groups chosen from the list halogen, CN, OH, and NO2.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl as just defined having 1 to 4 substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic group just defined having 1 to 4 substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cthioalkylxe2x80x9d is used herein to refer to the SR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the OR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the OR group, where R is aryl or substituted aryl, as defined above. The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the RCO group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, which may be either the same or different and the point of attachment is on the nitrogen atom The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, or I.
The compounds of this invention may be prepared according to the methods described below. 
According to scheme 1, commercially available oxindole 3 is treated with a strong organo-metallic base (e.g. butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (e.g. THF, diethyl ether) under nitrogen at reduced temperature (ca. xe2x88x9220xc2x0 C.) (Kende, et al, Synth. Commun., 12, 1, 1982) in the presence of lithium chloride or N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylene-diamine. The resulting di-anion is then treated with excess electrophile such as an alkyl halide, preferably an iodide. If RI and R2 are to be joined such as the product 4 contains a spirocycle at position 3, then the electrophile should be bifunctional, i.e. a diiodide. Subsequent bromination of 4 proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to afford the aryl bromide 5. The bromide 5 is reacted with a palladium salt (e.g. tetrakis(triphenylphoshine)palladium(0) or palladium acetate), in a suitable solvent (e.g. THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature under an inert atmosphere (argon, nitrogen). The mixture is then treated with an aryl or heteroaryl boronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions. The required product 6 is then isolated and purified by standard means.
Reaction of the indoline-2-one derivative 6 with either Lawessen""s reagent or phosphorous pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent provides access to the thiocarbonyl derivative 7. An additive such as sodium hydrogen carbonate may also be useful.
If R1 and R2 are different then the intermediate 4 is prepared by reacting the dianion of 3 with one equivalent of the electrophile RE1xe2x88x92X (X=leaving group e.g. iodine). The resultant mono-alkylated compound may then be isolated and re-subjected to the reaction conditions using R2xe2x88x92X, or alternatively used in-situ for the second alkylation with R2xe2x88x92X. Alternatively if the desired product 7 is to contain R2xe2x95x90H, then the isolated mono-alkylated intermediate is taken though the subsequent steps. 
Other methodologies are also available for coupling the pendant aryl or heteroaryl group, Ar, to the oxindole platform, for example reaction of compound 5 with an aryl or heteroaryl stannane, aryl or heteroaryl zinc, or aryl or heteroaryl magnesium halide in the presence of a palladium or nickel catalyst (scheme 2). The required aryl or heteroaryl-metallic species described above are formed through standard techniques.
Other functionalities can also be installed into the 3-position of the indoline platform according to scheme 3. Oxidation of the unsubstituted indoline 8, preferably under neutral or acidic conditions (e.g. selenium dioxide in dry dioxane at reflux) affords the isatin 9. Compound 9 may be further functionalized to provide a ketal 11 by treatment with an alcohol and acid catalyst under dehydrating conditions. Alternatively reaction of 9 with a second ketone under suitable conditions (piperidine in toluene at reflux; or TiCl4/Zn in THF at reflux) affords alkylidene derivatives 11. Reaction of the isatin 9 with a grignard reagent or organolithium affords tertiary alcohols 12 (Rxe2x95x90H). These alcohols may then be further functionalized by alkylation or acylation procedures. 
Reaction of the indoline-2-one derivative 6 with either Lawessen""s reagent or phosphorous pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent provides access to the thiocarbonyl derivative 7. An additive such as sodium hydrogen carbonate may also be useful. 
An alternative mode of preparation is to react compound 5 with either Lawessen""s reagent or phosphorous pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent, under an inert atmosphere (nitrogen or argon) providing access to the thiocarbonyl derivative 13. Then reaction of bromide 13 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (xe2x88x9250 to xe2x88x9220 xc2x0 C.) with n-butyllithium and N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine followed after a suitable period of time by a trialkylborate (trimethyl or triisopropylborate) gives after acidic work-up the boronic acid 14 (scheme 4). Compound 14 may then be reacted under palladium catalyzed conditions (tetrakis(triphenylphosphine)palladium(O) or palladium acetate, base (NaHCO3, Na2CO3, K2CO3, triethylamine, CsF) solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired compounds 7.
Alternatively reaction of compound 13 under palladium catalyzed conditions (tetrakis(triphenylphosphine)palladium(0) or palladium acetate, base (NaHCO3, Na2CO3, K2CO3, triethylamine, CsF) solvent (acetone/water, toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired compounds 7. 
Treatment of the bromide 5 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (xe2x88x9250 to xe2x88x9220xc2x0 C.) with n-butyllithium and N,N,N,Nxe2x80x2-tetramethylethylenediamine followed after a suitable period of time by a trialkylborate (trimethyl or triisopropylborate) gives after acidic work-up the boronic acid 15 (scheme 5). Compound 15 may then be reacted under palladium catalyzed conditions (tetrakis(triphenylphosphine)palladium(0), base (NaHCO3, Na2CO3, K2CO3, triethylamine, CsF) solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane)) with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate or aryl or heteroaryl fluorosulfonate, to provide the desired compounds 6.
An alternative strategy would be to prepare an organo zinc or magnesium reagent from compound 5 and react it in-situ with an aryl or heteroaryl bromide, aryl or heteroaryl iodide, aryl or heteroaryl trifluoromethane sulfonate of aryl or heteroaryl fluorosulfonate, under palladium catalyzed conditions to afford compound 6. Such an organo zinc or magnesium species could be prepared by treatment of the bromide 5 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (xe2x88x9250 to xe2x88x9220xc2x0 C.) with n-butyllithium and N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine followed after a suitable period of time by reaction with anhydrous zinc chloride or magnesium bromide.
Reaction of the indoline-2-one derivative 6 with either Lawesson""s reagent or phosphorous pentasulfide in a suitable organic solvent (pyridine, THF, dioxane, dimethoxyethane, dichloromethane, benzene, toluene, xylene) at a temperature between room temperature and the reflux temperature of the solvent, under an inert atmosphere (nitrogen or argon) provides access to the thiocarbonyl derivative 15. An additive such as sodium hydrogen carbonate may also be useful. 
According to scheme 6 thioamide derivatives 7 may be converted into enamine derivatives 16 (Wrobel, et al, J. Med. Chem, 1989, 2493).
Thus reaction of thioamide 7 (Pgxe2x95x90H, 2-(trimethylsilyl)-ethoxymethyl, benzyl, etc.) with triethyloxonium tetrafluoroborate followed by reaction with a nucleophile (nitromethane, cyanamide, trifluoromethanesulfonamide, Meldrum""s acid, etc.) followed by removal of the protecting group under appropriate conditions (e.g. tetrabutylammonium fluoride in THF for Pg=2-(trimethylsilyl)-ethoxymethyl) then gives the enamine derivatives 16. Appropriate solvents for the two steps are selected from dichloromethane, THF, dioxane, 1,2-dichloroethane, and the reaction is conducted at a temperature from xe2x88x9278xc2x0 C. to the boiling point of the solvent under an inert atmosphere (nitrogen or argon). 
According to Scheme 7, treatment of intermediate 7 with an alkylating agent, e.g., methyl iodide, ethyl iodide, 2,4-dinitrofluoro benzene, or 4-nitro fluorobenzene, in the presence of a suitable base (e.g. an amine base such as pyridine, triethylamine or di-iso-propylethylamine or lithium sodium, potassium or cesium carbonate) in a suitable organic solvent (e.g. DNW, THF, DMSO, dioxane or acetonitrile) at a temperature between xe2x88x9278xc2x0 C. and the boiling point of the solvent, would then afford thioimino ethers 17. Subsequent reaction of intermediates 17 with hydroxylamine or an acid salt of hydroxylamine (e.g. the hydrochloride) in a suitable solvent (for example but not limited to pyridine methanol, ethanol, iso-propanol, DMF, THF or DMSO and optionally in the presence of an additive such as a tertiary amine base or sodium or potassium acetate) at a temperature between xe2x88x9278xc2x0 C. and the boiling point of the solvent would then afford the N-hydroxyamidines 18.
Similarly treatment of intermediates 17 with a carbon nucleophile such as a malonate derivative (e.g., malononitrile, a cyano acetate ester, a nitro acetate ester or a malonate) in the presence of a suitable base (e.g. an amine base such as pyridine, triethylamine or di-iso-propylethylamine or lithium, sodium, potassium or cesium carbonate) or a Lewis acid (e.g. boron trifluoride etherate, a lead II salt, titanium tetrachloride, a magnesium II salt, or a silver salt) in a solvent compatible with the chosen base or Lewis acid (e.g. DMF, THF, DMSO, dioxane or acetonitrile, chloroform, benzene, toluene or dichloromethane) would then afford the adduct 19. If the group R3 in adduct 19 is an ester of a carboxylic acid, then it may be decarboxylated directly to give the enamine derivative 20 by treatment with, e.g. sodium iodide in DMSO at a temperature between room temperature and the boiling point of the solvent. Alternatively the ester may be first hydrolysed to the carboxylic acid (by treatment with an aqueous base (e.g. lithium sodium, or potassium hydroxide) in a suitable solvent (e.g. THF, dioxane acetonitrile, methanol or ethanol)), followed by decarboxylation in the presence of an acid (e.g. hydrochloric or sulfuric acid) in a suitable solvent (e.g. acetonitrile, THF, dioxane) to afford the derivatives 20. Alternatively the xanthate ester of the carboxylic acid may be prepared by reaction with a base such as sodium or potassium hydride in THF, followed by treatment with carbon disulfide. Subsequent reaction with tributyl tin hydride at elevated temperatures in a solvent such as benzene or toluene under an inert nitrogen or argon atmosphere in the presence of a radical initiator such as benzoyl peroxide or azo-bis-iso-butyronitrile would then give the product 20. 
An alternative strategy for synthesizing the product 18 is illustrated by Scheme 8. Thus the bromide 13 (the corresponding chloride, iodide or triflate ester may also be employed) is treated with an alkylating agent, eg methyl iodide, ethyl iodide, 2,4-dinitrofluoro benzene, or 4-nitro fluorobenzene, in the presence of a suitable base (e.g. an amine base such as pyridine, triethylamine or di-iso-propylethylamine or lithium, sodium, potassium or cesium carbonate) in a suitable organic solvent (e.g. DMF, THF, DMSO, dioxane or acetonitrile) at a temperature between xe2x88x9278xc2x0 C. and the boiling point of the solvent, would then afford thioimino ethers 21. Subsequent reaction of intermediate 21 with hydroxylamine or an acid salt of hydroxylamine (e.g. the hydrochloride, hydrobromide) in a suitable solvent (for example but not limited to pyridine methanol, ethanol, iso-propanol, DMF, THF or DMSO and optionally in the presence of an additive such as a tertiary amine base or sodium or potassium acetate) at a temperature between xe2x88x9278xc2x0 C. and the boiling point of the solvent, would then afford the N-hydroxyamidine 22. Intermediate 22 could then be protected with a compatible group (e.g. benzyl ether, acyl derivative, tetrahydropyranyl ether, methoxy methyl ether, silyl ether) to give the derivative 23. Alternately compound 21 could be reacted directly with a protected hydroxylamine derivative (chosen, but not limited to the protecting groups described above) to directly afford derivative 23. Compound 23 may then be reacted with a palladium salt (e.g. tetrakis(triphenylphoshine)palladium(0) or palladium acetate), in a suitable solvent (e.g. THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature under an inert atmosphere (argon, nitrogen). The mixture is then treated with an aryl or heteroaryl boronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions, and the reaction may then be heated to the boiling point of the solvent. The required product 24 is then isolated and purified by standard means.
Compound 24 may then be de-protected under the conditions prescribed by the nature of the protecting group. For example if the protecting group is a benzyl ether then treatment with boron tribromide or trimethylsilyl iodide in a suitable solvent (dichloromethane for example) would afford the compound 18. Other methods to remove the benzyl ether would involve hydrogenation (hydrogen gas or other hydrogen source such as cyclohexadiene or ammonium formate) in the presence of a palladium catalyst. Solvents suitable for such a process include methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature between room temperature and the boiling point of the solvent. If the protecting group was an acetal derivative (tetrahydropyranyl or methoxymethyl ethers) then hydrolysis could be effected under acidic conditions (hydrochloric acid, sulfuric acid, p-toluene sulfonic acid or acidic ion exchange resin) in a solvent such as methanol, ethanol, THF dioxane or acetonitrile. If the protecting group was an acyl derivative (acetate, or benzoate for example) then hydrolysis could be effected under acidic conditions as described above or under basic conditions (lithium sodium or potassium hydroxide) in a solvent such as an alcohol, THF, dioxane or acetonitrile at a temperature between room temperature and the boiling point of the solvent. If the protecting group was a silyl ether then compound 18 may be prepared by hydrolysing intermediate 24 under the acidic conditions described above or alternately by exposing compound 24 to a fluoride source (eg potassium fluoride, cesium fluoride or tetra butyl ammonium fluoride) in a solvent such as an alcohol, THF, dioxane or acetonitrile at a temperature between room temperature and the boiling point of the solvent. An inert atmosphere of nitrogen or argon may be necessary.
Another method of synthesizing compound 18 would be to convert the protected N-hydroxy amidine 23 into a boronic acid or boronic acid ester (by lithium halogen exchange followed by quench with tri-isopropyl borate, or palladium catalyzed coupling with diboron pinacolate) and then couple this boronic acid or ester derivative with an aryl chloride, bromide, iodide or triflate under a suitable palladium catalysis system as described previously. Subsequent deprotection as described for Scheme 8 would afford the desired compounds 18. 
According to Scheme 9, treatment of the N-hydroxyamidine 18 under reducing conditions (e.g. catalytic hydrogenation, iron in acetic acid or hydrazine-raney nickel) would then afford intermediate 25. Solvents suitable for such a process include methanol, ethanol, THF, ethyl acetate and dioxane, at a temperature between room temperature and the boiling point of the solvent. Protection of the secondary nitrogen (a tertiary butyl carbamate is shown as a non-limiting example) under standard conditions would then give compound 26. Reaction of compound 26 with an electrophilic cyanating agent (e.g. cyanogen bromide, N-cyanobenzotriazole or cyanogen bromide/4-dimethylaminopyridine complex) in a suitable solvent (THF acetonitrile or DMF, optionally in the presence of a base such as pyridine or sodium hydride or potassium tert-butoxide) may then afford the desired compound 27. In some cases the cyanation step may occur with concomitant removal of the secondary nitrogen protecting group, if this deprotection does not occur in-situ then a further hydrolysis step would be required.
An alternate synthesis of compound 27 may follow that of compound 18, Scheme 8, where an N-cyanoamidine bromide 28, prepared from compound 22 adopting a similar strategy to the reactions shown in scheme 9, could be coupled with a suitable functionalised aryl boronic acid or boronic acid ester to give compound 27. In another strategy intermediate 28 may be converted into the corresponding boronic acid or boronic acid ester and coupled in a Suzuki or Suzuki type palladium coupling with a suitable functionalised aryl bromide. 
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
This invention includes pharmaceutical compositions and treatments which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above, or a pharmaceutically acceptable salt thereof, as agonists of the progesterone receptor.
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists. These compounds may be used for contraception and post menopausal hormone replacement therapy.
The progesterone receptor agonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake.
When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.